Abstract
BackgroundA diverse repertoire of naïve T cells is thought to be essential for a robust response to new infections. However, a key aspect of aging of the T cell compartment is a decline in numbers and diversity of peripheral naïve T cells. We have hypothesized that the age-related decline in naïve T cells forces the immune system to respond to new infections using cross-reactive memory T cells generated to previous infections that dominate the aged peripheral T cell repertoire.ResultsHere we confirm that the CD8 T cell response of aged, influenza-naïve mice to primary infection with influenza virus is dominated by T cells that derive from the memory T cell pool. These cells exhibit the phenotypic characteristics of virtual memory cells rather than true memory cells. Furthermore, we find that the repertoire of responding CD8 T cells is constrained compared with that of young mice, and differs significantly between individual aged mice. After infection, these virtual memory CD8 T cells effectively develop into granzyme-producing effector cells, and clear virus with kinetics comparable to naïve CD8 T cells from young mice.ConclusionsThe response of aged, influenza-naive mice to a new influenza infection is mediated largely by memory CD8 T cells. However, unexpectedly, they have the phenotype of VM cells. In response to de novo influenza virus infection, the VM cells develop into granzyme-producing effector cells and clear virus with comparable kinetics to young CD8 T cells.
Highlights
A diverse repertoire of naïve T cells is thought to be essential for a robust response to new infections
In response to de novo influenza virus infection, the virtual memory (VM) cells develop into granzyme-producing effector cells and clear virus with comparable kinetics to young CD8 T cells
Since our results demonstrated that the vast majority of the responding CD8 T cells that develop in the aged mice in response to influenza infection were from the population of VM cells, it was important to determine if these cells were capable of effector function
Summary
A diverse repertoire of naïve T cells is thought to be essential for a robust response to new infections. The decline in naïve T cells with aging has been correlated with impaired immunity and reduced ability to respond to new infections [3,4,5,6, 13, 22, 23]. Consistent with this, our previous studies confirmed that declining numbers of naïve CD8 T cells in aged mice correlated with poor responses to de novo infection with influenza virus [7]. We further showed that the naïve precursor frequency of NP-specific CD8 T cells was 10-fold lower than PA-specific CD8 T cells in aged mice, providing an explanation for the selective decline in the immune response to influenza virus NP. This study provided proof of Lanzer et al Immunity & Ageing (2018) 15:17 concept that the naïve repertoire to epitopes with a low precursor frequency may become so constrained during aging that “holes” develop in the repertoire [7]
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